Breast Cancer Program (BCP) PROJECT SUMMARY The main goals of the Breast Program (BCP) are to advance the understanding of breast cancer development and the prevention and treatment of breast cancer, to facilitate intra-programmatic and inter-programmatic interactions, and to provide an enriched learning environment for students and post-doctoral medical and laboratory-based trainees. The program has 25 members (21 research members. 2 clinical members, and 2 adjunct members). BCP includes both a strong basic science group and a clinical breast center that has a large and active clinical and translational program. Faculty are members from seven different Departments/Centers. A new Director has been recruited for the Breast Center, Dr. Matthew Ellis, an internationally renowned physician scientist who will strengthen an important component of the BCP where genomics and proteomics are applied to tissues from patients enrolled in neoadjuvant studies. In the basic science component, both animal models and human breast cell line and patient derived xenograft models are employed to examine the mechanisms underlying the origin and progression of breast cancer. The Breast Program is organized around four Research Themes: 1. Mechanisms of resistance to therapy. 2. Stem cells in normal mammary gland development and breast cancer progression; 3. Estrogen receptor and other signaling pathways in development, prevention and progression of breast cancer, and 4. Development of new preclinical metastasis models. Translation to the clinic is an integral component of all of these themes. The program has a total of $15.7M of which $13.2M is peer reviewed including $7.9 million from the NCI. In the last 4 years members of the program published 220 cancer related manuscripts in peer-reviewed journals of which 22% represented intra-programmatic collaborations and 31% inter-programmatic. Major accomplishments include: 1. Defining the role of mammary epithelial stem cells and EMT pathways in resistance to chemotherapy, 2. The delineation of combination therapies in HER2 + breast cancers leading to the first rationale combination target therapies clinical trial performed in the absence of chemotherapy, 3. Deciphering the mechanisms of resistance to hormonal and HER2 targeted therapies, specifically for the latter elucidating the role of PTEN loss and PI3K mutations, and 4. The use of new model systems for prevention and drug development studies leading to two clinical trials to study the effects of a JAK2 inhibitor Ruxolitinib to prevent pregnancy?s promotion of breast cancer, and Crizotinib and Sunitinib in metastatic triple negative breast cancer.